Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Similarly, diabetes mellitus is characterized by insulin deficiency or resistance. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Notably, arcuate POMC and NPY/AgRP neurons are key targets of leptin and insulin action. Moreover, normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC and NPY/AgRP neurons are involved in this hypothalamic stress response. In the current proposal, we will extend prior observations. We will identify cellular mechanisms through which ER stress induces acute leptin and insulin resistance. We will also determine a role for ER stress in identified hypothalamic neurons to regulate metabolism.